Naltrexone is currently used in oral tablet form as an adjunct in the treatment of alcohol dependence, as well as to help maintain opioid addicts in a drug-free state. Transdermal delivery of naltrexone is desirable in order to help reduce side effects associated with oral therapy and improve compliance. Naltrexone itself does not have the essential physicochemical properties that would allow a therapeutic dose of the drug to cross the human skin barrier. This problem may be solved by designing and synthesizing derivatives (co-drugs) which are more skin permeable than naltrexone. A co-drug or mutual pro-drug consists of two synergistic drugs chemically linked together, in order to improve the drug delivery properties of one or both drugs. Bupropion, a successful smoking cessation treatment, is the drug chosen for linkage to naltrexone. Simultaneous treatment of alcohol and tobacco addiction is vital, because of the biochemical and behavioral causal links in this common co-morbidity, as well as alcoholics' high death rate from tobacco-related diseases. Opioid addicts may also benefit from this treatment combination, because of their high prevalence of smoking and co-abuse. The hypothesis is that chemical combinations of naltrexone and bupropion in a co-drug form will improve the transderrnal delivery rate of the drugs. The specific aims of this project are: (1) to synthesize a series of naltrexone, 6-beta-naltrexol, bupropion, and hydroxybupropion codrugs designed to elucidate quantitative structure-activity relationships (QSARS) for transdermal flux and subsequent bioconversion rates, (2) to characterize the physicochemical properties of the co-drugs, including molecular volume, lipophilicity, hydrogen-bonding potentials, melting points, heats of fusion, hydrolysis kinetics, and solubilities in select solvents, (3) to measure the co-drugs' penetration and bioconversion rates in human skin in vitro, and (4) to characterize the pharmacokinetics of the co-drugs in guinea pigs in vivo. These objectives will help to identify the critical parameters involved in the optimization of transdermal co-drug designs. Correlation of the in vitro data with the in vivo model will aid in the creation of a reliable QSAR database that is necessary to help identify the best co-drugs for clinical use.